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Phosphorylation of Immunity-Related GTPases by a Toxoplasma gondii-Secreted Kinase Promotes Macrophage Survival and Virulence
Open accessAbstract
SUMMARY Macrophages are specialized to detect and destroy intracellular microbes and yet a number of pathogens have evolved to exploit this hostile niche. Here we demonstrate that the obligate intracellular parasite Toxoplasma gondii disarms macrophage innate clearance mechanisms by secreting a serine threonine kinase called ROP18, which binds to and phosphorylates immunity-related GTPases (IRGs). Substrate profiling of ROP18 revealed a preference for a conserved motif within switch region I of the GTPase domain, a modification predicted to disrupt IRG function. Consistent with this, expression of ROP18 was both necessary and sufficient to block recruitment of Irgb6, which was in turn required for parasite destruction. ROP18 phosphorylation of IRGs prevented clearance within inflammatory monocytes and IFN-γ-activated macrophages, conferring parasite survival in vivo and promoting virulence. IRGs are implicated in clearance of a variety of intracellular pathogens, suggesting that other virulence factors may similarly thwart this innate cellular defense mechanism.
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Cites
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Vetter, I. R., & Wittinghofer, A. (2001) · Science · doi:10.1126/science.1062023 · Cited by 1,875
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Efficient Gene Disruption in Diverse Strains of Toxoplasma gondii Using CRISPR/CAS9
Shen, B., Brown, K. M., Lee, T. D., & Sibley, L. D. (2014) · mBio · doi:10.1128/mbio.01114-14 · Cited by 473
Self-citationInnate immunity to Toxoplasma gondii infection
Yarovinsky, F. (2014) · Nature Reviews Immunology · doi:10.1038/nri3598 · Cited by 462
Toxoplasma Effectors Targeting Host Signaling and Transcription
Hakimi, M.-A., Olias, P., & Sibley, L. D. (2017) · Clinical Microbiology Reviews · doi:10.1128/cmr.00005-17 · Cited by 339
Self-citationMechanisms of Toxoplasma gondii persistence and latency
Sullivan, W. J., & Jeffers, V. (2012) · FEMS Microbiology Reviews · doi:10.1111/j.1574-6976.2011.00305.x · Cited by 259
Metadata
- Authors
- Fentress, S. J., Behnke, M. S., Dunay, I. R., Mashayekhi, M., Rommereim, L. M., Fox, B. A., Bzik, D. J., Taylor, G. A., Turk, B. E., Lichti, C. F., Townsend, R. R., Qiu, W., Hui, R., Beatty, W. L., & Sibley, L. D.
- Venue
- Cell Host & Microbe
- Publisher
- Elsevier BV
- Published
- 2010-12
- Volume
- 8
- Issue
- 6
- Pages
- 484-495
- ISSN
- 1931-3128 (ISSN-L)
- OpenAlex
- W1970998121
- Cited by
- 319
- References
- 1
- FWCI
- 19.27
- Type
- journal article
- Language
- en
- Open access
- bronze
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- The paper
- Fentress, S. J., Behnke, M. S., Dunay, I. R., Mashayekhi, M., Rommereim, L. M., Fox, B. A., Bzik, D. J., Taylor, G. A., Turk, B. E., Lichti, C. F., Townsend, R. R., Qiu, W., Hui, R., Beatty, W. L., & Sibley, L. D. (2010). Phosphorylation of Immunity-Related GTPases by a Toxoplasma gondii-Secreted Kinase Promotes Macrophage Survival and Virulence. Cell Host & Microbe. https://doi.org/10.1016/j.chom.2010.11.005
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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